Non-medullary thyroid cancer (TCA), the most common type of endocrine malignancy, accounts for most deaths due to endocrine cancers. Although the majority of TCAs are successfully managed with surgery and radioactive iodine (I-131) ablative therapy, the mortality associated with this disease has remained stable over the years because these therapies are not effective for clinically aggressive tumors. The latter group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs, which have accelerated patterns of growth and/or fail to trap iodine efficiently. The loss of iodine trapping ability by the malignant thyrocyte may be correlated with other cellular and molecular events that accompany de-differentiation. Our goal is to study the molecular events accompanying the natural history of clinically aggressive TCA and the response of various molecular markers to standard therapeutic intervention(s). Preoperative diagnostic methods include aspiration cytology, ultrasonography, thyroid scanning with I-131 and/or other radionuclides, and suppression therapy with L-thyroxine. Specific issues include: (i) optimization of methods of diagnostic scanning in TCA and serum thyroglobulin (Tg) measurement to diagnose tumor recurrence, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio, (iii) PCR-based detection and quantification of thyroid-specific mRNAs (e.g. thyroglobulin mRNA and mRNAs for other markers) in thyrocytes circulating in peripheral blood, (iv) analysis of mutations in genes involved in TCA growth, apoptosis, and mitotic cycle regulation, such as the thyrotropin receptor, ras, p53, Fas/Fas ligand, and ret/PTC in primary and metastatic thyroid tumors, and (v) establishment of immortalized cell lines from human TCAs for in vitro studies. The relationship between the level of expression of markers of differentiation, as well as mutations in growth-relevant genes, and the clinical behavior of TCA will help further define the pathways responsible for thyrocyte growth and differentiation. Over the last year, we have studied the level of expression of sodium-iodide symporter (NIS) in renal metastases from thyroid primaries in patients with papillary TCA-Follicular Variant and correlated them with in vivo I-131 uptake. Further, we have reviewed 31 years of NIH (single institution) experience in 20 patients who underwent extensive secondary surgical resections of distant and locoregional metastases in an attempt to better define their role in the multimodality management of patients with "clinically aggressive" TCA. Additionally, in collaboration with our NCI colleagues, we have investigated the effects of a novel pro-differentiating agent, depsipeptide, in the induction of differentiation (i.e. expression of Tg and NIS mRNAs), and tumoricidal activity in poorly-differentiated TCA cell lines in vitro. Our preliminary data were encouraging for the role of this agent, as well as other similar agents, clinically. In fact, we are currently developing interventional trials aiming to revert aggressive TCAs to a more differentiated phenotype, by the induction/re-emergence of previously inexistent or the increase in currently insufficient iodine accumulation by the tumor, and thus rendering them yet again manageable by 131-I.